In FY2019 we have made progress in the following areas: 1). Multiple sclerosis is an inflammatory demyelinating autoimmune disorder affecting the central nervous system whose severity is reduced using immune suppressive drugs. Therapeutic intervention with interferon-beta reduces disease exacerbations and delays relapses. The receptor for type 1 interferon, IFNAR, is present on virtually all cell types making it difficult to dissect the mechanisms involved. We generated mice with a conditional deletion (cKO) of IFNAR in Treg cells (IFNARfl/flFoxp3cre). RNA seq analysis revealed little differences between steady state Treg cells from WT and cKO mice. Yet cKO mice developed severe EAE with an earlier onset than control mice. Although Treg cells from cKO mice appeared to be more activated, the activation status and effector cytokine production of CD4+ and CD8+T cells in the draining lymph nodes (dLN) was similar in WT and cKO mice during the priming phase, but higher in cKO CD4 T cells in the effector phase. Interestingly, we noted a substantial reduction of myeloid derived suppressor cells (MDSCs) in the dLN of cKO mice, while generation of MDSCs in bone marrow and recruitment to spleen of WT and cKO mice was comparable. CD4+ T cells from cKO mice were found to be defective in chemokine secretion suggesting that IFNAR signaling on Treg cells modulates the capacity of CD4+ T cells to secrete MDSC recruiting chemokines during the priming phase. While modulation of Treg cell number and function by MDSCs has been documented, this study is one of the first to demonstrate that Treg cells may modulate MDSC homing and raises the possibility of a novel role for Treg cells in regulating the kinetics of MDSC recruitment during inflammatory conditions. 2). While TCR-MHC interactions are crucial for antigen recognition and induction of specific immune responses, all T cells have the potential to recognize self in the absence of foreign antigen. We have previously demonstrated that blockade of TCR-MHCII interactions in vivo resulted in a marked disturbance of immune homeostasis with expansion of memory phenotype (MP) Treg, CD4+Foxp3-, and CD8+ T cells. To explore whether MHCI interactions also played a role in immune homeostasis, we treated unmanipulated mice with a pan-anti-H-2 mAb for 6 days. Surprisingly, this treatment resulted in marked expansion of NK cells, MP CD8+ T cells and to a lesser extent MP CD4+ T cells. All the effects of the anti-MHCI treatment were critically dependent on the presence of NK cells. Activated NK cells secreted high amounts of IFN-gamma which induced high levels of MHCI and MHCII expression on APC as well as IL-15 secretion by APC. IL-15 subsequently drove MP CD4+ and CD8+ T cell proliferation as well as NK cell expansion. The global disruption of immune homeostasis induced by blockade of MHCI interactions created an environment that rendered the animals resistant to the growth of several transplanted tumors. In addition, treatment of mice with both acute and chronic LCMV infection resulted in enhanced viral clearance. Taken together, disruption of the interaction of NK cells with their MHCI targets in the steady state can paradoxically result in beneficial activation of immune responses against viruses and tumors. Blocking of MHC-I interactions by anti-MHCI could also be useful to better understand immune responses against intracellular (viruses) and extracellular (bacteria) pathogens and the generation of long-term memory responses.